Pathogenic SPTBN1 variants cause a novel autosomal dominant neurodevelopmental syndrome

SPTBN1 encodes {beta}II-spectrin, the ubiquitously expressed member of the {beta}-spectrin family that forms micrometer-scale networks associated with plasma membranes. {beta}II-spectrin is abundantly expressed in the brain, where it is essential for neuronal development and connectivity. Mice deficient in neuronal {beta}II-spectrin expression have defects in cortical organization, global developmental delay, dysmorphisms, and behavioral deficiencies of corresponding severity. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous variants in this gene may also present with measurable compromise of neural development and function. Here we report the identification of heterozygous SPTBN1 variants in 29 individuals who present with global developmental, language and motor delays, mild to severe intellectual disability, autistic features, seizures, behavioral and movement abnormalities, hypotonia, and variable dysmorphic facial features. We show that these SPTBN1 variants lead to loss-of-function, gain-of-function, and dominant negative effects that affect protein stability, disrupt binding to key protein partners, and affect cytoskeleton organization and dynamics. Our studies define the genetic basis of this new neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and neural development, and underscore the critical role of {beta}II-spectrin in the central nervous system.